Human Immunodeficiency Virus (HIV) was first established as the viral agent that causes acquired immunodeficiency syndrome (AIDS) in humans 36 years ago [CDC (Centers for Disease Control and Prevention, US). Pneumocystis pneumonia-Los Angeles. Morbidity and Mortality Weekly Report (MMWR) 1981; 30: 250-252.]. More than 70 million people have been infected with HIV, and about half of them have died since 1981 [WHO (World Health Organization). Global Health Observatory (GHO) data: HIV/AIDS. www.who.int/gho/hiv/en/; retrieved on 11 Oct. 2017]. In China, the number of HIV infections increased more than 39 times from 2008 to August, 2017, and the death rate is more than 30% [ MSCID (Monthly Statistics of China Infectious Diseases); www.nhfpc.gov.cn/jkj/s3578/201709/d30e75fc9d2e4d09ab01279662b16b96.shtml; retrieved on 11 Oct. 2017]. AIDS has been ranked as the leading cause of death among the infectious diseases in China since 2007 [NHFPC (National Health and Family Planning Commission of the People's Republic of China). China Health Statistics Yearbook 2014, 22-14; www.stats.gov.cn/tjsj/ndsj/2014/indexch.htm, retrieved on 11 Oct. 2017]. Although today's anti-HIV drugs have significantly extended the life span of HIV-positive people in wealthy countries [UNAIDS. UNAIDS Data 2017. www.unaids.org/sites/default/files/media_asset/20170720_Data_book_2017_en.pdf], they have side effects and diminishing effectiveness due to the development of viral resistance [WHO (World Health Organization), CDC (Centers for Disease Control and Prevention) and The Global Fund. HIV drug resistance report 2017]. Since there are no drugs capable of curing at present, nor vaccine available to prevent this viral disease, the discovery and development of new anti-HIV drugs are very much needed and the undertaking of such studies are imperative.
Avian flu gained widespread attention in 1997 when cases of human infection from the H5N1 subtype of avian influenza were reported in Hong Kong. Since 2003, human H5N1 infected cases have been reported every year. As of Jul. 25, 2017, a total of 859 human H5N1 infected cases have been confirmed in 16 countries with a mortality rate greater than 50% [WHO 2017. Cumulative number of confirmed human cases for avian influenza A (H5N1) reported to WHO, 2003-2017. www.who.int/influenza/human_animal_interface/EN_GIP_20130705CumulativeNum berH5N1cases_2.pdf].
Historically, pandemics have been caused by the introduction of a wholly avian virus or an avian-human reassortant, to which human populations lack immunity (Russell C J, Webster R G. The genesis of a pandemic influenza virus. Cell. 2005; 123: 368-71). In the 20th century, three major pandemics occurred: in 1918 (Spanish Flu), 1957 (Asian Flu), and 1968 (Hong Kong influenza). The largest and most deadly pandemic in recorded history occurred in 1918 with an estimated death toll of more than 40 million people worldwide, which was caused by an H1N1 subtype influenza A virus [Basler C F, Reid A H, Dybing J K, Janczewski T A, Fanning T G, Zheng H, et al. Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses bearing the 1918 NS genes. Proc Natl Acad Sci USA. 2001; 98: 2746-51]. The deadly outbreaks of the H1N1 “swine flu” in 2009 [Gibbs A J, Armstrong J S, Downie J C. From where did the 2009 ‘swine-origin’ influenza A virus (H1N1) emerge? Virol J. 2009; 6: 207] and the H7N9 avian influenza A in 2013 [WHO 2013. Number of confirmed human cases for avian influenza A (H7N9) reported to WHO, report 10, data in WHO/HQ as of 25 Oct. 2013. www.who.int/influenza/human_animal_interface/influenza_h7n9/10u_ReportWebH7 N9Number.pdf] have caused alarm worldwide.
Influenza virus H5N1 (a subtype of influenza A virus) is an avian pathogen that originally circulated in wild birds without causing disease. The virus jumped to poultry flocks in Southeast Asia at an unknown time, causing only mild symptoms of disease in birds (Fauci A S. Emerging and re-emerging infectious diseases: influenza as a prototype of the host-pathogen balancing act. Cell. 2006; 124: 665-70). As the virus infected chickens and other domestic poultry, it mutated to its current highly pathogenic form. In general, as avian influenza viruses do not replicate efficiently in humans, direct transmission of avian viruses to humans is probably an extremely rare event [Beigel J H, Farrar J, Han A M, Hayden F G, Hyer R, de Jong M D, et al. Avian influenza A (H5N1) infection in humans. N Engl J Med. 2005; 353: 1374-85]. However, two research groups successfully produced modified H5N1 virus in the separate laboratories in 2012. The genetically modified viruses are capable of acquiring the capacity for airborne transmission among mammals [Imai M, Watanabe T, Hatta M, Das S C, Ozawa M, Shinya K, et al. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature. 2012; 486: 420-8; Herfst S, Schrauwen E J A, Linster M, Chutinimitkul S, Wit E, Munster V J, et al. Airborne transmission of influenza A/H5N1 virus between ferrets. Science. 2012; 336: 1534-41]. The studies demonstrated the possibility that naturally occurring H5N1 avian influenza virus may one day mutate to become airborne and transmissible to humans. Thus, there is a need to prepare for potential pandemics caused by future strains influenza viruses.
A pandemic caused by H5N1 is considered more dangerous in comparison with those caused by other types of influenza viruses due to high mortality rates of patients infected by H5N1. An ideal way to combat the avian influenza virus in humans is to block or at least reduce the likelihood of interspecies transfer, and this requires a comprehensive, multifaceted approach (Peiris J S M, Poon L L M, Guan Y. Surveillance of animal influenza for pandemic preparedness. Science. 2012; 335: 1173-4). Antivirals form an important part of this approach. Neuraminidase (NA) inhibitors efficiently blocked the NA activity of the 2004 H5N1 viruses in vitro, indicating their potential effectiveness in influenza chemotherapy and prophylaxis against H5N1 virus infection. However, recent isolation of resistant mutants against these compounds has emphasized the need for careful monitoring to control potential pandemic influenza. For example, most seasonal strains of influenza, including H5N1, now exhibit resistance to amantadine and amantadine. The 2004 H5N1 Vietnam and Thailand isolates were resistant to amantadine, because of mutations in the M2 gene segment (Li K S, Guan Y, Wang J, Smith G J, Xu K M, Duan L, et al. Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature. 2004; 430: 209-13) and this limits the use of amantadine and amantadine derivatives for controlling potential pandemics [Govorkova E A, Baranovich T, Seiler P, Armstrong J, Burnham A, Guan Y, et al. Antiviral resistance among highly pathogenic influenza A (H5N1) viruses isolated worldwide in 2002-2012 shows need for continued monitoring. Antivir. Res. 2013; 98: 297-304]. These events highlight the urgent need for development of new antivirals. Thus, there is a need to identify and develop novel treatment for viral infections, such as HIV, AIDS, and influenza.